Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

Testosterone use as anabolic therapy is controversial. Here, meta-analyses show that testosterone increases skeletal muscle mass and strength in androgen-deficient young men, older men and men with chronic illness; these data provide a compelling rationale for the development of selective androgen receptor modulators that mimic testosterone's effects without its side effects. Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging. Key Points Meta-analyses of clinical trials provide unequivocal evidence that testosterone administration increases skeletal muscle mass, muscle strength, and leg power; these anabolic effects of testosterone are dose-related The effects of testosterone supplementation on physical function and clinical outcomes in older men with physical dysfunction and in men with chronic illness are unknown Testosterone induces skeletal muscle fiber hypertrophy and increases the number of satellite cells Testosterone increases muscle mass and decreases fat mass by promoting the diff